 Entero-toxigenic ischaricicoli, ETEC, subtypes that produce heat-stable entero-toxin, ST, are a major cause of diarrhea-related illness and death among children under five in low and middle-income countries. Recent studies suggest that adding an ST-toxoid would complement ongoing ETEC vaccine development efforts, but the poor immunogenicity of ST has complicated its advancement. However, recent progress in screening for optimal mutants, mapping cross-reacting epitopes, and improving carrier-coupling strategies enables the rational design of safe, immunogenic, and well-defined ST-based vaccine candidates. This article was authored by Ephraim Debebe Zegai, Morten Leessinger Vasli, Harba Somerfeldt, and others.